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Biomolecules
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Advances in Protein-Ligand Interactions: From Structure, Function to Applications
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Advances in Protein-Ligand Interactions: From Structure, Function to Applications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Structure and Dynamics".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 5060

Special Issue Editor

Dr. Mateusz Banach

E-Mail Website1 Website2
Guest Editor
Department of Bioinformatics and Telemedicine, Faculty of Medicine, Jagiellonian University Medical College, Medyczna 7, 30-688 Kraków, Poland
Interests: bioinformatics; computational geometry; computer science; data analysis; data visualization; hydrophobic core; optimization algorithms; protein folding; protein-protein interaction; python programming; web services and databases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins do not dwell in the void. Quite the opposite—their cellular environment is crowded with molecules. Likewise, many biological processes depend on the interaction between proteins and their neighborhood. They can form complexes with other proteins, small molecules, ions, nucleic acids and nearby fragments of the cell membrane. While we typically equate the word “ligand” with members of the small compound category, depending on the context, this nomenclature can be extended to the other types of complex partners as well.

The understanding and the prediction of the protein–ligand interactions (PLIs) lie at the foundation of the drug discovery process. To check whether the specific compound achieves the desired biological activity, one must perform an in vitro experiment. However, due to the large number of candidates (available from the various drug libraries), exhaustive screening in the lab is both time-consuming and prohibitively costly. Computational methods allow us to tackle this issue by narrowing the search space down to a manageable number of the most promising solutions. The ever-growing amount of chemical and biological data evokes new research opportunities, but also the need for the improvement of the PLI analysis and prediction approaches.

In this Special Issue, we collate reports on current advancements in the area of protein–ligand interaction. This includes, but is not limited to, protein surface exploration, binding site recognition, docking algorithms, molecular dynamics, de novo drug design, ADME studies, application of machine learning frameworks and the results of clinical trials.

Dr. Mateusz Banach
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bioinformatics
  • compound libraries
  • computational biology
  • de novo drug design
  • drug discovery
  • ligand binding
  • machine learning
  • molecular docking
  • molecular dynamics
  • protein complexes

Published Papers (4 papers)

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Research

20 pages, 4609 KiB  
Article
In Silico Study of Camptothecin-Based Pro-Drugs Binding to Human Carboxylesterase 2
by Frank Beierlein, Anselm H. C. Horn, Heinrich Sticht, Andriy Mokhir and Petra Imhof
Biomolecules 2024, 14(2), 153; https://doi.org/10.3390/biom14020153 - 27 Jan 2024
Viewed by 975
Abstract
Pro-drugs, which ideally release their active compound only at the site of action, i.e., in a cancer cell, are a promising approach towards an increased specificity and hence reduced side effects in chemotherapy. A popular form of pro-drugs is esters, which are activated [...] Read more.
Pro-drugs, which ideally release their active compound only at the site of action, i.e., in a cancer cell, are a promising approach towards an increased specificity and hence reduced side effects in chemotherapy. A popular form of pro-drugs is esters, which are activated upon their hydrolysis. Since carboxylesterases that catalyse such a hydrolysis reaction are also abundant in normal tissue, it is of great interest whether a putative pro-drug is a probable substrate of such an enzyme and hence bears the danger of being activated not just in the target environment, i.e., in cancer cells. In this work, we study the binding mode of carboxylesters of the drug molecule camptothecin, which is an inhibitor of topoisomerase I, of varying size to human carboxylesterase 2 (HCE2) by molecular docking and molecular dynamics simulations. A comparison to irinotecan, known to be a substrate of HCE2, shows that all three pro-drugs analysed in this work can bind to the HCE2 protein, but not in a pose that is well suited for subsequent hydrolysis. Our data suggest, moreover, that for the irinotecan substrate, a reactant-competent pose is stabilised once the initial proton transfer from the putative nucleophile Ser202 to the His431 of the catalytic triad has already occurred. Our simulation work also shows that it is important to go beyond the static models obtained from molecular docking and include the flexibility of enzyme–ligand complexes in solvents and at a finite temperature. Under such conditions, the pro-drugs studied in this work are unlikely to be hydrolysed by the HCE2 enzyme, indicating a low risk of undesired drug release in normal tissue. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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12 pages, 1436 KiB  
Article
Molecular Insight into Ligand Binding and Transport by the Lentil Lipid Transfer Protein Lc-LTP2: The Role of Basic Amino Acid Residues at Opposite Entrances to the Hydrophobic Cavity
by Daria N. Melnikova, Ivan V. Bogdanov, Andrey E. Potapov, Anna S. Alekseeva, Ekaterina I. Finkina and Tatiana V. Ovchinnikova
Biomolecules 2023, 13(12), 1699; https://doi.org/10.3390/biom13121699 - 24 Nov 2023
Viewed by 844
Abstract
Lipid transfer proteins (LTPs) realize their functions in plants due to their ability to bind and transport various ligands. Structures of many LTPs have been studied; however, the mechanism of ligand binding and transport is still not fully understood. In this work, we [...] Read more.
Lipid transfer proteins (LTPs) realize their functions in plants due to their ability to bind and transport various ligands. Structures of many LTPs have been studied; however, the mechanism of ligand binding and transport is still not fully understood. In this work, we studied the role of Lys61 and Lys81 located near the “top” and “bottom” entrances to the hydrophobic cavity of the lentil lipid transfer protein Lc-LTP2, respectively, in these processes. Using site-directed mutagenesis, we showed that both amino acid residues played a key role in lipid binding to the protein. In experiments with calcein-loaded liposomes, we demonstrated that both the above-mentioned lysine residues participated in the protein interaction with model membranes. According to data obtained from fluorescent spectroscopy and TNS probe displacement, both amino acid residues are necessary for the ability of the protein to transfer lipids between membranes. Thus, we hypothesized that basic amino acid residues located at opposite entrances to the hydrophobic cavity of the lentil Lc-LTP2 played an important role in initial protein–ligand interaction in solution as well as in protein–membrane docking. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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21 pages, 3457 KiB  
Article
The Blocking of Drug Resistance Channels by Selected Hydrophobic Statins in Chemoresistance Human Melanoma
by Wojciech Placha, Piotr Suder, Agnieszka Panek, Patrycja Bronowicka-Adamska, Marta Zarzycka, Małgorzata Szczygieł, Jacek Zagajewski and Monika Weronika Piwowar
Biomolecules 2023, 13(12), 1682; https://doi.org/10.3390/biom13121682 - 21 Nov 2023
Viewed by 1151
Abstract
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, [...] Read more.
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model (Mus musculus SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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26 pages, 12805 KiB  
Article
Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders
by Danish Iqbal, Mohammed Alsaweed, Qazi Mohammad Sajid Jamal, Mohammad Rehan Asad, Syed Mohd Danish Rizvi, Moattar Raza Rizvi, Hind Muteb Albadrani, Munerah Hamed, Sadaf Jahan and Hadeel Alyenbaawi
Biomolecules 2023, 13(11), 1613; https://doi.org/10.3390/biom13111613 - 04 Nov 2023
Viewed by 1366
Abstract
Neurodegenerative disorders, such as Alzheimer’s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal [...] Read more.
Neurodegenerative disorders, such as Alzheimer’s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A–N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3β, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3β (ΔG: −8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M−1), NMDA (ΔG: −9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M−1), and BACE-1 (ΔG: −9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M−1). It showed a 25-fold higher affinity with GSK-3β, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3β-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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